Project Summary Inappropriate interpersonal aggression is a common and serious symptom of social dysfunction in multiple psychiatric disorders, including Schizophrenia, Alzheimer's Disease, ADHD, Autism, and Major Depression, among others. Despite the widespread prevalence of abnormal aggressive behavior in psychiatric patient, few effective treatments currently exist. Underlying this unfortunate dearth of treatments is a lack of comprehensive knowledge of the neural processes controlling aggressive behavior. Interestingly, recent neuroimaging studies in humans suggest that elevated aggression in psychiatric patients may result, in part, from the inappropriate activation of reward circuitry. Data in rodents corroborates this notion with a vast literature describing a functional role for the mesolimbic dopamine system in the repeated subordination of male conspecifics, an experience that induces ?escalated aggression? phenotypes in a small portion of individual mice and mirrors the pathological aggressive behavior observed in a small portion of human psychiatric patients. While hugely relevant to the processes underlying escalated aggression, the specific mechanisms controlling the motivational or rewarding components of escalated aggression remain largely unknown. Evidence from our laboratory suggests that the lateral habenula (lHb), a small region of the epithalamus crucial for providing negative regulation of ventral tegmental area (VTA) dopamine release, plays an important role in controlling the valence of aggressive encounters. However, much still remains unknown about the mechanisms modulating lHb activity in the context of aggression and aggression reward. The hypothalamic neuropeptide orexin represents an attractive candidate for providing this modulatory role, as it has been implicated in a wide range of relevant behaviors including reward, arousal, stress, and social interaction. While orexin neurons send sizeable projections to the lHb, this circuit has never been examined in any behavioral domain. In this proposal, I will investigate the cell-type specific regulation of orexin receptor expression in the lHb by aggression. I will then utilize viral-mediated gene transfer techniques to knock down lHb orexin receptor expression in a cell-type specific manner to determine the functional importance of this receptor in mediating aggression and aggression reward. The results of these studies will inform our understanding of the mechanisms controlling affective components of aggression and reveal novel target mechanisms for therapeutic development.